Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage.
Christina BeckDeepak RamanujamPaula VaccarelloFlorenc WidenmeyerMartin FeuerherdCho-Chin ChengAnton BomhardTatiana AbikeevaJulia SchädlerJan-Peter SperhakeMatthias GrawSeyer SafiHans HoffmannClaudia A Staab-WeijnitzRoland RadUlrike ProtzerThomas FrischmuthStefan EngelhardtPublished in: Nature communications (2023)
Recent studies of severe acute inflammatory lung disease including COVID-19 identify macrophages to drive pulmonary hyperinflammation and long-term damage such as fibrosis. Here, we report on the development of a first-in-class, carbohydrate-coupled inhibitor of microRNA-21 (RCS-21), as a therapeutic means against pulmonary hyperinflammation and fibrosis. MicroRNA-21 is among the strongest upregulated microRNAs in human COVID-19 and in mice with acute inflammatory lung damage, and it is the strongest expressed microRNA in pulmonary macrophages. Chemical linkage of a microRNA-21 inhibitor to trimannose achieves rapid and specific delivery to macrophages upon inhalation in mice. RCS-21 reverses pathological activation of macrophages and prevents pulmonary dysfunction and fibrosis after acute lung damage in mice. In human lung tissue infected with SARS-CoV-2 ex vivo, RCS-21 effectively prevents the exaggerated inflammatory response. Our data imply trimannose-coupling for effective and selective delivery of inhaled oligonucleotides to pulmonary macrophages and report on a first mannose-coupled candidate therapeutic for COVID-19.
Keyphrases
- sars cov
- oxidative stress
- pulmonary hypertension
- coronavirus disease
- inflammatory response
- liver failure
- respiratory syndrome coronavirus
- high fat diet induced
- endothelial cells
- adipose tissue
- dna methylation
- mouse model
- aortic dissection
- room temperature
- electronic health record
- wild type
- cancer therapy
- human immunodeficiency virus
- hiv infected
- induced pluripotent stem cells
- replacement therapy
- quantum dots
- acute respiratory distress syndrome
- loop mediated isothermal amplification